Derivatives of quinoxalinone



United States Patent 3,361,747 DERIVATIVES 0F QUINGXALINQNE Gerhard R. Wendt, Havertown, and Kurt W. Ledig, Philadelphia, Pa., assignors to American Home Products (Zorporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 10, 1964, Ser. No. 395,585 18 Claims. (Cl. 260-250) This invention is concerned with compounds classified in the art of chemistry as cyclopentaquinoxalinones and benzocyclopentaquinoxalinones.

As determined by standard tests in warm blooded animals, these compounds exhibit potent anti-inflammatory activity.

The claimed compounds can be represented by the general formula:

In the above general formula, W is one of the moieties shdwn below:

and

R is selected from the group of (lower)alkyl, halo(:lower) alkylphenyl, phenyl, benzyloxy(lower) alkyl, nitrophenyl, (lower)alkylphenyl, benzyl, halophenyl, and (lower)alkoxyphenyl, where the substituent may be in the 0-, m-, or p-positions on the phenyl ring. R and R are selected from the group of hydrogen, chlorine, fluorine, bromine and methyl, except that when both R and R are hydrogen, and R is lower alkyl, R has more than one carbon atom in the alkyl chain and, also, when both R and R are hydrogen R is not phenyl. As used herein the term lower refers to both straight-chained and branched hydrocarbon groups containing from 1 to 4 carbon atoms therein.

The claimed compounds are prepared by the reaction shown below:

which is acid-catalyzed with acetic acid or with a mineral acid.

Patented Jan. 2, 1968 (1 where R is as above.

Similarly, it will be understood that when the trione starting material is reacted with a 1,2-diaminonaphthalene the product is a benzo[f]cyclopenta[b]quinoxalin-9-one of the formula:

where R is as above. Finally, it should be noted that reaction of the described trione with an o-phenylenediamine in the maner described herein, leads to the production of a cyclopenta[b]quinoxalin-Z-one which has the formula:

wherein R, R and R are as above stated. v

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms, singly, or, in combination with other coacting compounds. They can if desired be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed, or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid composition can take the form of solutions, emulsions, suspensions, syrups, or elixirs. Such conventional solid carriers as sucrose, starches, etc., or liquid vehicles such as non-toxic alcohols, glycerine, or the like, may be thus used.

When so administered by oral or intraperitoneal routes in doses of from 5 to 200 mg./kg. of body weight the compounds of the invention will moderate and alleviate inflammatory disorders. Moreover, their utility, in addition to the specific area noted, also extends to the area of veterinary medicine as well as experimental pharmacology.

The following examples will serve to further illustrate the invention in its various product and process aspects. These several examples are purely exemplary of the in- 3 vention and are not intended to limit its concept in any manner.

Example 1.6,7-dimethyl-1,3-dihydrO-1-pr0pyZ-2H- cyclopenta [b] quinoxalin-Z-one To 250 ml. of a solution containing 5.0 g. of 3-propyl- 1,2,4-cyclopentanetrione was added a solution of 5.0 g. of 4,5-dimethyl-o-phenylenediamine in 100 ml. of alco- 1101 and 400 ml. of water. The reaction mixture was brought to a boil and after cooling, the precipitate was filtered oflf. Recrystallization from alcohol afforded the desired product; M.P. 290 C. (dec.). (Found: C, 75.62; H, 7.34; N, 10.96. C H N O requires: C, 75.56; H, 7.13; N, 11.02%.)

Example 2.--6,7-dichZora-1,3-dihydr-1-pr0pyl-2H- cyclopenta [b] quinoxalin-Z-one To 250 m1. of a solution containing 5.0 g. of 3-propyl- 1,2,4-cyclopentanetrione was added asolution of 5.0 g. of 4,5-dichloro-o-phenylenediamine in 800 ml. water and 100 ml. alcohol. The resulting solution was brought to a boil and let stand at 25 overnight. The precipitate was filtered and recrystallized from 150 ml. of dimethylformamide to yield 5.3 g. of the title compound, M.P. 290 C. (dec.). (Found: C, 57.29; H, 4.12; N, 9.80; Cl, 24.00. C H Cl N O requires: C, 56.95; H, 4.19; N, 9.49; Cl, 24.03

Example 3.-6,7-dichl0r0-I,3-dihydr0-1-methyl-2H- cycl0penta[b]quinoxalin-Z-one A hot aqueous solution of 6.0 g. of 3-rnethyl-1,2,4- cyclopentanetrione in 200 ml. of water was treated with a solution of 5.0 g. of 4,S-dichloro-o-phenylenediamine in 200 ml. of alcohol and 20 ml. of glacial acetic acid. The reaction mixture was heated for a few minutes; the resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 3.6 g. of the title compound; M.P. 350 C. (Found: C, 54.31; H, 2.75; Cl, 26.20; N, 10.76. C H Cl N O requires: C, 54.14; H, 3.03; Cl, 26.29; N, 10.53%.)

Example 4.-6,7-dichl0r0-1,3-dihydr0-1-(Z-benzyloxyethyl) -2H-cycl0penta [b] quinoxalin-Z-one A suspension of 2.0 g. of 2-(2-benzyloxyethyl)-4-phenylimino-1,3-cyclopentanedione, (prepared as disclosed in copending application U.S. Ser. No. 351, 8 1 6), 125 ml. of 2 N sulfuric acid, and m1. of alcohol was refluxed for 4 hours. The resulting solution containing 3-(2-benzyloxyethyl)-1,2,4-cyclopentanetrione was then refluxed with a solution of 3.0 g. of 4,5-dichloro-o-phenylenediamine in 100 m1. of alcohol for a few minutes. The precipitate was filtered and recrystallized from acetic acid to give the title compound melting at 230 C. (dec.). (Found: C, 61.75; H, 4.15; N, 7.56; CI, 18.3. C H CI N O requires: C, 62.03; H, 4.17; N, 7.24; C], 18.31%.)

Example 5.1,3-dihydr0-6,7-dimethyl-1-methyl- ZH-cyclopenta [b] quinoxalin-Z-one To 100 ml. of a boiling aqueous solution of 3-methylcyclopentane-1,2,4-trione was added 5.0 g. of 4,5-dimethyl-o-phenylenediamine in 100 ml. of 95% alcohol and, 10 ml. acetic acid and the reaction mixture allowed to stand at 25 overnight. The precipitate was filtered and recrystallized from 200 ml. acetic acid to obtain 1.5 g. of the title compound; dec. 316320 C. (Found: C, 74.13; H, 6.36; N, 12.09. C H N O requires: C, 74.31; H, 6.24; N, 12.38%.)

Example 6.-6,7-dichl0ro-1,3-dihydr0-1-ethyl-2H- cycl0penta[b] quinoxalin-Z-one An aqueous solution (300 ml.) of 5.0 g. of 3-ethyl-1, 2,4-cyclopentanetrione was refluxed with a solution of 4,S-dichloro-o-phenylenediamine in 200 ml. of alcohol and 20 ml. of glacial acetic acid for a few minutes. The resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 3.6 g. of the title compound;

4 melting at 316-318 C. (dec.). (Found: C, 55.61; H, 3.54; Cl, 25.10; N, 10.20. C H Cl N O requires: C, 55.54; H, 3.59; Cl, 25.23; N, 9.97%.)

Example 7. -J ,3 -dihydro-6,7-dimethyl-1 -ethyl-2 H- cyclopenta [b] quinoxalin-Z-one To 250 ml. of an aqueous solution containing 5.0 g. of 3-ethylcyclopentane-1,2,4-trione was added 5.0 g. of 4,5- dimethyl-o-phenylenediamine in 100 ml. 95 alcohol and 20 ml. acetic acid. On heating the reaction mixture to the boiling point a material precipitated which after standing overnight was filtered and recrystallized from 275 ml. dimethyl formamide to give 4. 9 g. of the title compound, melting at 2-92295 C. (Found: C, 74.92; H, 6.57; N, 11.75. C H N requires: C, 74.97; H, 6.71; N, 11.66%.)

Example 8.1-butyl-I,3-dihydr0-2H-cycl0penta [b] quinoxalin-Z-one To 250 ml. of an aqueous solution containing 5.0g. of 3 butyl-cyclopentane-1,2,4-trione was added 4.7 g. of o-phenylenediamine in 100 ml. 95 alcohol and 10 ml. of acetic acid. The reaction mixture was brought to a boil and let stand at 25 C. overnight. The precipitate was filtered and recrystallized from 150 ml. of dimethyl formamide to give 5.7 g. of the title compound; M.P. 260- 262 C. (Found: C, 75.10; H, 6.68; N, 11.48. C H N O requires: C, 74.97; H, 6.71; N, 11.66%.)

Example 9.1-butyl-6,7-diclzl0r0-Z,3-dihydr0-2H- cycl0pe:zta[b] quinoxalin-Z-one To ml. of an aqueous solution containing 3.0 g. of 3-butylcyclopentane-1,2,4-trione was added 1.8 g. of 4,5- dichloro-o-phenylenediamine in 36 ml. of alcohol and 3.6 ml. glacial acetic acid. The solution was brought to a boil and let stand at 25 C. overnight. The precipitate Was filtered and recrystallized from 50 ml. dimethylformamide to obtain 1.5 g. of the title compound, M.P. 280-281 C. (Found: C, 59.76; H. 4.65; N, 9.33; Cl,

22.6. C H Cl N O requires: c, 57.96; H, 4.65; N, 9.33; 0

Example 10.1-butyl-1,3-dihydr0-6,7-dimethyl-2H- cyclopenta[b]'quin0xalin-2-0ne To 250 ml. of an aqueous solution containing 5.0 g. of 3-buty1cyclopentane-1,2,4-trione was added a solution of 5.0 g. of 4,5-dimethyl-o-phenylenediamine in ml. of 95 alcohol and 10 ml. of acetic acid. The solution was brought to a boil and let stand at 25 C. overnight. The precipitate was filtered and recrystallized from 300 ml. dimethylforrnamide to obtain 3.3 g. of the title compound which decomposes at 285 C. (Found: C, 75.74; H, 7.74; N, 10.56. C l-I N O requires: C, 76.08; H, 7.51; N, 10.44%.)

The same procedures of the above examples are employed to prepare the compounds listed in the following table using the appropriate starting compounds. This list is given to avoid unnecessary repetition of experimental details.

Example N0. Formula R R R Benzyl Hydrogen" Hydrogen. p-Methoxyphenyl do Do. o-Butoxy-phenyl--. -do Do. p-Tnfluoro- Bromine. Bromine methylphenyl. m-OhlorophenyL- do D0. 4-b enzyloxybutyL. Hydrogen Hydrogen rn-Nitrophenyl d Do. m-ChlorophenyL Chloro Chloro.

p-Bromophenyl. Hydrogem. Hydrogen. o-Tol 1 ..do Do. m-Butylphenyl. .do Do. 3-benzyloxy- Methyl- Methyl.

propyl. Phenyl Br0mine Bromine. do Fluorine- Fluorine.

Example 23 .1 ,3-dihydr-1 -methyl-2H-benzo[ g] cyclopenta[ b] quinoxalin-Z-one To a boiling aqueous solution of 6.0 g. of 3-methylcyclopentane-1,2,4-trione was added 5.0 g. of 2,3-diamino-naphthalene in 200 ml. 95% alcohol and ml. glacial acetic acid. The reaction mixture was allowed to stand at 25 overnight. Recrystallization of the precipitate from dimethylformamide gave 1.1 g. of the title compound Which decomposes at 345 C. (Found: C, 77.25; H, 4.69; N, 11.00. C H N O requires: C, 77.40; H, 4.87; N, 11.28%.)

Example 24 .1 ,3-dilzydro-1 -etlzy I-ZH-benzo [g] cyclopen ta [b] quinoxalin-Z -one An aqueous solution (300 ml.) of 5.0 g. of 3-ethylcyclopentane-l,2,4-trione was refluxed with a solution of 5.0 g. of 2,3-diaminonaphthalene in 200 ml. of alcohol and ml. of acetic acid. The resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 4.5 g. of the title compound; M.P. 318 C. (dec.). (Found: C, 77.76; H, 5.45; N, 10.43. C H ON requires: C, 77.84; H, 5.38; N, 10.68%.)

Example 25.-1,3-dihydr0-I-pr0pyl-2H-benzo[g] cyclopenta[b]qainoxalin-Z-one An aqueous solution (300 ml.) of 5.0 g. of 3-propylcyclopentane-1,2,4-trione was refluxed with a solution of 5.0 g. of 2,3-diaminonaphthalene in 200 ml. of alcohol and 20 ml. of acetic acid for a few minutes. The resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 5.5 g. of the title compound; M.P. 310 C. (dec.). (Found: C, 78.02; H, 5.59; N, 10.22. C H N O requires: C, 78.23; H, 5.84; N, 10.14%.)

Example 26.1,3-dihydro-1-butyl-2H-benzo [g] cyclopenta [b] quinoxalin-Z-one To 250 ml. of a boiling solution containing 5.0 g. of 3-butylcyclopentane-l,2,4-trione was added 5.0 g. of 2,3- diaminonaphthalene in 200 ml. 95% alcohol and the reaction mixture let stand at overnight. Recrystallization of the precipitate from 100 ml. of dimethylformamide gave 2.2 g. of the title compound; dec. 280 C. (Found: C, 78.23; H, 6.21; N, 9.79. C H N O requires: C, 78.59; H, 6.25; N, 9.65%.)

Example 27.1,3-dihydr0-1-(Z-benzyloxyethyl) -2H- benzo [g] cyclopenta [b] qainoxalin-Z-one A suspension of 2.0 g. of 2-(2-benzyloxyethyl)-4- phenylimino-1,3-cyclopentadione (prepared as disclosed in US. Ser. No. 351,816), 125 ml. of 2 N sulfuric acid, and 25 ml. of alcohol was refluxed for 4 hours. The resulting solution containing 3-(2-benzyloxyethyl)-1,2,4- cyclopentanetrione was then refluxed with a solution of g. of 2,3-diaminonaphthalene in 75 ml. of alcohol for a few minutes. The resulting precipitate was filtered and recrystallized from dimethyl formamide to give the title compound: M.P. 235-237 C. (dec.). (Found: C, 78.10; H, 5.21; N, 7.30. C I-1 N 0 requires: C, 78.24; H, 5.47; N, 7.60%.)

The same procedures of the above examples are employed to prepare the compounds listed in the following table using the appropriate starting compounds. This list is given to avoid unnecessary repetition of experimental details.

Example No. Formula Benzyl. p-Methoxyphenyl. o-Butoxyphenyl. p-Trifiuoromethylphenyl. m-Chlorophenyl. 4-benzyloxybutyl. m-Nitrophenyl. p-Chlorophenyl. p-Bromophenyl. o-Tolyl.

m-Butylphenyl.

a-benzyloxypropyl. Phenyl.

6 Example 40.-8,10-dihydro-lO-ethyl-9H-benz0 [f] cyclopenta [b] quinoxalin-Q-one An aqueous solution (300 ml.) of 5.0 g. of 3-ethylcyclopentane-1,2,4-trione was refluxed with a solution of 5.0 g. of 1,2-diaminonaphthalene in ml. of alcohol and 20 ml. of acetic acid for a few minutes. The resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 2.8 g. of the title compound; M.P. 319 C. (dec.). (Found: C, 77.86; H, 5.37; N, 10.43. C H ON requires: C, 77.84; H, 5.38; N, 10.68%

Example 41 .-8,10-dihydro-l0-pr0pyl-9H-benz0 [f] cyclopema [b qainoxalin-9-one An aqueous solution (300 ml.) of 5.0 g. of 3-propylcyclopentane-1,2,4-trione was refluxed with a solution of 5.0 g. of 1,2-diaminonaphthalene in 100 ml. of alcohol and 20 ml. of acetic acid for a few minutes. The resulting precipitate was filtered and recrystallized from dimethyl formamide to yield 1.6 g. of the title compound, M.P. 295 C. (dec.). (Found: C, 78.23; H, 5.84; N, 10.13. C H ON requires: C, 78.23; H, 5.84; N, 10.14%.)

The same procedure of Examples 40 and 41 is employed to prepare the compounds listed in the following table using the appropriate starting compounds.

Example No. R

Benzyl. p-Methoxyphenyl. o-Butoxyphenyl. p-Trifluoromethylpheuyl.

m-Chlorophenyl. 4-Benzyloxybutyl. m-Nitrophenyl. p-Chlorophenyl. p-Bromophenyl.

o-Tolyl. m-Butylphenyl.

3benzyloxypr0pyl.

1b Pheny 55 1b l pFlu0rophenyl.

What is claimed is:

1. 1,3 dihyd-ro-6,7-dimethyl-1-propyl-2H-cyclopenta- [b] quinoxalin-Z-one.

2. 6,7 dichloro-1,3-dihydro-l-propyl-ZH-cyclopenta- [b] quinoxalin-Z-one.

3. 6,7 dichloro-1,3-dihydro-l-methyl-ZH-cyclopenta- [b]quinoxalin-2-one.

4. 6,7 dichloro-1,3-dihydro-1-(2-benzyloxyethyl)-2H- cyclopenta [b] quinoxalin-2-one.

5. 1,3 dihydro-6,7-dimethyl-l-methyl-ZH-cyclopenta- [b] quinoxalin-Z-one.

6. 6,7 dichloro-1,3-dihydro-1-ethyl-2H-cyclopenta[b]- quinoxalin-Z-one.

7. 1,3 dihydro 6,7-dimethyl-1-ethy1-2H-cyclopenta- [b] quinoxalin-Z-one.

8. 1 butyl-l,3-dihydro-2H-cyclopenta[b]quinoxalin- 2-one.

9. 1 buty1-6,7-dichloro-1,3-dihydro-2H-cyclopenta[b]- quinoxalin-Z-one.

10. 1 buty1-1,3-dihydro-6,7-dirnethyl-2H-cyclopenta- [b] quinoxalin-Z-one.

11. 1,3 dihydro-l-methyl-ZH-benzo[g] cyclopenta[b]- quinoxalin-Z-one.

12. 1,3 dihydro-l-ethyl-ZH-benzo[g]cyc1openta[b]- quinoxalin-Z-one.

13. 1,3 dihydro-l-propyl-ZH-benzo[g]cyclopenta[b]- quinoxa1in-2-one.

14. 1,3 dihydro-l-butyl-ZH-benzo[g]cyclopenta[b]- 15. 1,3 dihydro-l-(2-benzyloxyethyl)-2H-benzo[g]- cy clopenta [b] quinoxalin-Z-one.

16. 8,10 dihydro-10-ethyl-9H-benzo[f]cyclopenta[b]- quinoxalin-9-one.

17. 8,10 dihydro-l0-propyl-9H-benzo[f]cyclopenta [b] quinoxalin-9-one.

18. A compound selected from the group consisting of those having the formulae:

wherein R is selected from the group consisting of (lower) alkyl, benzyloxy( lower alkyl, (lower) alkylphenyl, (lower) alkoxyphenyl, halo(lower)alkylphenyl, nitrophenyl, benzyl, phenyl and halophenyl; and R and R are selected from the group consisting of hydrogen, chlorine, bromine, fluorine and methyl, except that when both R and R are hydrogen, and R is an alkyl group, said alkyl group has at least two carbon therein, and when both R and R are hydrogen, R is not phenyl.

References Cited UNITED STATES PATENTS 3,311,626 3/1967 Wendt et a1. 260-250 NICHOLAS S. RIZZO, Primary Examiner. 

18. A COMPOUND SELECTED FROM THE GROU CONSISTING OF THOSE HAVING THE FORMULAE: 